Enhancer-Driven lncRNA BDNF-AS Induces Endocrine Resistance and Malignant Progression of Breast Cancer through the RNH1/TRIM21/mTOR Cascade

Lin, Xiaorong; Dinglin, Xiaoxiao; Cao, Siting; Zheng, Senyou; Wu, Cheng-Hung; Chen, Wenying; Li, Qingjian; Hu, Qian; Zheng, Fang; Wu, Zhi‐Yong; Lin, De–Chen; Yao, Yihong; Xu, Xiaoding; Xie, Zhi; Liu, Qiang; Yao, Herui; Hu, Hai

doi:10.1016/j.celrep.2020.107753

Cited by 66 publications

(46 citation statements)

References 48 publications

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“…Luminal type is the most common type, accounting for 60%-70% of all breast cancer types [12,13]. TAM is the main treatment drug for Luminal breast cancer, but during the treatment, many patients will develop resistance to TAM, including primary resistance and secondary resistance [14]. MLF1IP plays an integral part in the pathogenesis of breast cancer and may also be associated with the resistance.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanism of Secondary Endocrine Resistance in Luminal Breast Cancer

Ding

Wen

et al. 2021

BioMed Research International

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Objective. The molecular mechanism of secondary resistance in Luminal breast cancer was studied to provide new ideas for the treatment of breast cancer. Methods. The sensitivity of the downregulation of myeloid leukemia factor 1-interacting proteins (MLF1IP) to Tamoxifen (TAM) was tested by the Cell Counting Kit-8 (CCK-8). The apoptosis of MLF1IP-mediated resistance was analyzed by flow cytometry (FCM) with/without TAM. Western blot was used in detecting various kinds of apoptosis and the expression of the protein related to the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway to study the molecular mechanism of secondary endocrine resistance in Luminal breast cancer. Results. The downregulation of MLF1IP could significantly increase the drug sensitivity of Michigan Cancer Foundation-7 (MCF-7) cells and also inhibit the proliferation of MCF-7 cells under the stimulation of drugs. Western blot results showed that the expression of Bcl-2-associated X (BAX), Caspase3, Caspase7, and Caspase9 proteins increased when MLF1IP was downregulated. The results of the PI3K/AKT signaling pathway revealed that the phosphatase and tensin homolog deleted on chromosome ten (PTEN) protein expression of MCF7-shRNA was higher than that of MCF7-NC cells, while the expression of p-AKT was lower than that of MCF7-NC cells. Conclusions. (1) MLF1IP-related apoptosis resistance plays an essential role in MLF1IP-mediated secondary resistance of breast cancer cells. (2) MLF1IP promotes AKT phosphorylation by inhibiting the PTEN expression, thus activating the PI3K/AKT signaling pathway and causing the secondary resistance of Luminal breast cancer. (3) MLF1IP can be used as a factor to predict the endocrine resistance of Luminal breast cancer.

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Section: Discussionmentioning

confidence: 99%

Molecular Mechanism of Secondary Endocrine Resistance in Luminal Breast Cancer

Ding

Wen

et al. 2021

BioMed Research International

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“…Xiaorong Lin's study showed that lncRNA BDNF-AS (NR_033312) promoted RNH1 ubiquitination degradation in TRIM21-dependent manner to induce poor outcomes and endocrine therapy resistance of breast cancer, thereby leading to malignant progression. 21 FGD5-AS1 (NR_046252) enhanced nonsmall cell lung cancer cells' proliferation through regulating FGD5-AS1/has-miR-107/FGFRL1 axis, 22 and Fu et al's study also demonstrated that FGD5-AS1 improved cisplatin resistance of non-small cell lung cancer cells through miR-140-5p/WEE1 signaling pathway. 23 Moreover, other malignant tumors have also been reported to correlate with high FGD5-AS1 expression.…”

Section: Discussionmentioning

confidence: 95%

Comprehensive Analysis of Peritoneal Metastasis Sequencing Data to Identify LINC00924 as a Prognostic Biomarker in Gastric Cancer

Fang¹,

Huang²,

Han³

et al. 2021

CMAR

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Background: Gastric cancer peritoneal metastasis has high mortality. At present, there is no effective way to cure the patients diagnosed with gastric cancer peritoneal metastasis due to its indistinct molecular mechanism. Therefore, to understand the pathogenesis and help for further target therapy, we conduct comprehensive analysis of peritoneal metastasis by bioinformatics in gastric cancer. Methods: Microarray sequencing was used to find differential mRNAs and long non-coding RNAs (lncRNAs) expression between primary foci and peritoneal metastases lesion in gastric cancer. RT-qPCR was used to verify the expression levels of lncRNAs in gastric cancer cells after co-culture with adipocytes. TCGA, Cytoscape, lnCAR, cBioPoratal and R packages (ggrisk, survival, survminer, timeROC, forestplot, immunedeconv, ggplot2, pheatmap and ggpubr) were applied in this work. Results: Adipocytes co-culture model was used to mimic the peritoneal microenvironment and found that LINC01151 (NR_126348), FAM27B (NR_027422) and LINC00924 (NR_027133) were up-regulated in co-culture group. Increased LINC00924 expression was significantly associated with reduced overall survival and up-regulated percentage abundance of tumorinfiltrating CD8 + T, B, macrophage and NK immune cells; moreover, immune checkpoint blockers (ICBs) had a worse effect on the LINC00924 high expression group. Furthermore, through univariate and multivariate Cox regression analysis, we found that LINC00924-related PEX5L in CNC network was an independent prognostic factor in gastric cancer progression. Conclusion: LINC00924 expression was associated with poor survival, immune infiltrations and worse response to ICBs. LINC00924 might be immunotherapeutic targets of advanced gastric cancer.

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“…LncRNA BDNF-AS was reported to promote breast cancer progression by functioning as a scaffold RNA, supporting RNH1 ubiquitination by the E3 ligase TRIM21 and thus RNH1 degradation. This relieves mTOR mRNA suppression by RNH1 and promotes cell-proliferation associated mTOR signalling and thus cancer progression [89]. In non-small-cell lung cancer cells, lncRNA MetaLnc9 was found to promote cell migration and invasion.…”

Section: Lncrna Involvement In the Ubiquitin-proteasome Systemmentioning

confidence: 99%

Emerging Roles of Long Noncoding RNAs in the Cytoplasmic Milieu

Aillaud

Schulte

2020

ncRNA

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While the important functions of long noncoding RNAs (lncRNAs) in nuclear organization are well documented, their orchestrating and architectural roles in the cytoplasmic environment have long been underestimated. However, recently developed fractionation and proximity labelling approaches have shown that a considerable proportion of cellular lncRNAs is exported into the cytoplasm and associates nonrandomly with proteins in the cytosol and organelles. The functions of these lncRNAs range from the control of translation and mitochondrial metabolism to the anchoring of cellular components on the cytoskeleton and regulation of protein degradation at the proteasome. In the present review, we provide an overview of the functions of lncRNAs in cytoplasmic structures and machineries und discuss their emerging roles in the coordination of the dense intracellular milieu. It is becoming apparent that further research into the functions of these lncRNAs will lead to an improved understanding of the spatiotemporal organization of cytoplasmic processes during homeostasis and disease.

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Enhancer-Driven lncRNA BDNF-AS Induces Endocrine Resistance and Malignant Progression of Breast Cancer through the RNH1/TRIM21/mTOR Cascade

Abstract: Highlights d BDNF-AS induces tamoxifen resistance and malignant progression of breast cancers d BDNF-AS driven by MEF2A-regulated enhancer acts as scaffold of RNH1/TRIM21 d BDNF-AS activates mTOR pathway by abolishing RNH1regulated mTOR mRNA decay

Cited by 66 publications

References 48 publications

Molecular Mechanism of Secondary Endocrine Resistance in Luminal Breast Cancer

Molecular Mechanism of Secondary Endocrine Resistance in Luminal Breast Cancer

Comprehensive Analysis of Peritoneal Metastasis Sequencing Data to Identify LINC00924 as a Prognostic Biomarker in Gastric Cancer

Emerging Roles of Long Noncoding RNAs in the Cytoplasmic Milieu

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